Separatory devices useful in biomedical applications such as kidney dialysis, hemodialysis, hemoultrafiltration, blood oxygenation and the like are well known. Such devices generally consist of at least one separatory membrane or element, disposed in a housing or casing having an inlet and an outlet means. The separatory membrane may take the form of a hollow fiber, film, screen, and the like and is chosen for its ability to perform the intended biomedical function.
While various methods of manufacture of such separatory devices have been described, certain of such methods employ potting or sealing resins to secure the separatory membranes in the housing and prevent the mixing of fluids which pass on either side of the membrane when necessary.
The suitability of the potting resin for use in a separatory device is governed by a number of criteria which can best be illustrated with reference to separatory devices which employ hollow fibers.
Such devices typically consist of a plurality of permeable hollow fibers whose terminal portions are potted in a sealing collar and extend therethrough, thereby providing liquid access to the interior of the fibers.
The separatory elements are then typically sealed within a casing to form a separatory cell having one or more liquid ports which allow for the passage of one fluid, such as blood, through the fibers and another fluid around the fibers without mixing the two fluids. The separatory element may have two sealing collars or a single sealing collar in which latter case the fibers are doubled back so that all the ends terminate together. The general configuration of the separatory element and separatory cell is similar to a tube-and-shell heat exchanger.
Patents representative of the art of hollow fiber separatory devices include U.S. Pat. Nos. 2,972,349; 3,228,876; 3,228,877; 3,339,341; 3,442,088; 3,423,491; 3,503,515; 3,551,331 the disclosures of which are herein incorporated by reference.
The sealing collar is typically derived from a resin which is capable of encapsulating the fibers to provide a seal which prevents the fluid inside the hollow fibers from mixing with the fluid outside the fibers.
A preferred class of resins useful for preparing the sealing collars are flexible polyurethane forming systems as illustrated by U.S. Pat. Nos. 3,362,921; 3,708,071; 3,722,695; 3,962,094 and 4,031,012 the disclosures of which are herein incorporated by reference. Centrifugal casting, as illustrated by U.S. Pat. No. 3,492,698, the disclosure of which is herein incorporated by reference, is a representative method employed for preparing sealing collars. In accordance with such a technique, a holding device containing a bundle of fibers arranged in a parallel configuration is placed into a centrifugal-like device which incorporates a potting-material reservoir with tubes connecting it to end-molds. An appropriate resin is placed into the potting reservoir maintained at an appropriate temperature. The entire assembly is then rotated to force the resin down the connecting tubes by the centrifugal force. The resin thereby flows around and among the fibers in the end-molds. The rotation is continued until the resin gels. When polyurethanes are employed as the resin, typical residence time in the centrifuge can vary from about 1 to about 2 hours at room temperature. When rotation is completed the resin impregnated fiber bundle is removed and post-cured. The end molds are then removed and the fiber ends are opened by cutting through the resin collar perpendicular to the fiber bundle.
Other sealing collar forming techniques rely on the force of gravity to force the resin into a mold containing the ends of the hollow fibers. The resin is allowed to gel and then is post-cured.
Regardless of the particular method employed for preparing the sealing collar the polyurethanes typically employed therein exhibit extended gel, and demold times.
The same polyurethane resins that are employed in preparing hollow fiber separatory devices are used to perform similar functions in other separatory devices wherein a separatory membrane is provided in a configuration different from that of hollow fibers. Thus, while the configuration of the separatory membranes differ in commercially available separatory devices, the problems of extended cure times are common to all.
In many instances known catalysts that are specific for increasing the hydroxyl-isocyanate reaction rate such as aliphatic and cycloaliphatic tertiary amines, and soluble metal compounds, particularly organotin compounds are employed to increase the generally slow curing time of the polyurethane.
The selection of a suitable catalyst for use in a polyurethane system intended as a potting resin for a biomedical device is complicated by the requirement that the resin system be non-toxic. Thus, the aliphatic and cycloaliphatic tertiary amines are unsuitable because of their toxicity and their use would present a danger that they might be released into the fluids which pass through the separatory device during its operation. Although tin-octoate has been used as a catalyst and is non-toxic it is hydrolytically unstable and must be added to the polyol on site rather than during packaging of the polyol. Ferric acetyl acetonate can also be used as a catalyst but it is toxic at levels of about 0.1% by weight and higher and imparts a dark red color to the polyurethane.
Thus, it would be a distinct advantage if the polyurethane forming composition inherently exhibited a reduced cure time, i.e., gel time and post cure time, even in the absence of a catalyst. This would eliminate the danger posed by incorporation of large amounts of catalysts which can be released into the separatory device.
The choice of a suitable potting resin in the preparation of a separatory device intended for use in a biomedical application is further complicated by the fact that such a resin should optimally also exhibit a number of other important properties such as an acceptably low viscosity, the proper balance between density, flexibility and bonding properties so that the intended sealing effect is achieved e.g., the interior portions of the hollow fibers embedded therein are capable of being hermetically sealed off from the external environment. As described above, the polyurethane must also be non-toxic. This is achieved when the components are completely cured so that residual reactants cannot be released into the fluids which will pass through the separatory device.
The polyurethane should also exhibit avoidance of gas evolution during solidification, a minimum or no change in volume during cure, and a minimum evolution of heat during cure.
The requirement that a potting resin exhibit low viscosity, like the requirement that it exhibit a reduced cure time is a major economic concern. A low mix viscosity of the polyurethane forming system would enable the resin to penetrate efficiently and quickly around and among the hollow fibers when using, for example, the centrifugal casting technique described above. The combination of properties possessed by a polyurethane forming system of low cure time and low viscosity, therefore, would substantially improve the economic efficiency of processes employing the same used in preparing separatory devices.
It is known that polyurethanes may be formed from the reaction of an isocyanate-terminated prepolymer with a lactone derived polyester polyol. Lactone derived polyester polyols may be prepared by reacting a lactone with a polyfunctional alcohol. Such lactone polyesters are well-known and are disclosed in U.S. Pat. Nos. 2,977,385; 3,523,101; 3,591,561; 3,660,357; and 3,663,515, the disclosures of which are herein incorporated by reference as well as British patent specification No. 1,076,871; Belgian Pat. No. 817,879; Japanese Pat. No. 76-76,388; and German Auslegeschrift No. 1,936,587. For example, U.S. Pat. No. 2,977,385 discloses lactone adducts which are useful in preparing polyurethanes, as plasticizers, and as intermediates for preparing elastomers and foams. The lactone adducts are prepared by reacting a lactone having at least six carbon atoms in the ring with any of a number of initiators. These initiators include monofunctional alcohols, monofunctional amines, diols and higher functional alcohols, polyamines, etc. The use, however, of polyurethanes prepared from such lactone adducts as potting compositions in separatory devices is not disclosed in any of the above patents.
The search has therefore continued for ways to improve the cost efficiency of separatory devices intended for use in biomedical applications and processes for preparing the same. The present invention is a result of this search.